Citations

Molecular reductionism has so far failed to deliver the broad-based therapeutic insights that were initially hoped for. This form of reductionism is now being replaced by so-called “systems biology.” This is a nebulously defined approach and/or discipline, with some versions of it relying excessively on hypothesis-neutral approaches and only minimally informed by key physiological concepts such as homeostasis and regulation. In this context, physiology is uniquely positioned to continue to provide impressive levels of both biological and therapeutic insight by using hypothesis-driven “classical” approaches and concepts to help frame what might be described as the “pieces of the puzzle” that emerge from molecular reductionism. The strength of physiology as a “bridge” between reductionism and epidemiology, along with its unparalleled ability to generate therapeutic insights and opportunities justifies increased attention and emphasis on our discipline into the future. Arguments relevant to this set of assertions are advanced and this paper, which was based on the 2011 Adolph Lecture, represents an effort to fill the intellectual void left by reductionism and improve scientific progress.

Abstract Allogeneic hematopoietic stem cell (HSC) transplantation is a promising area of therapy for various hematological malignancies like chronic/acute myeloid leukemia, myelodysplasia and lymphomas. Its effectiveness at inducing the graft versus tumor (GVT) effect is however, compromised by the graft versus host disease (GVHD) frequently observed in recipients post transplant. One of the strategies utilized in minimizing the effect of GVHD while still preserving GVT activity has been to target immunosuppressive cell types like Treg cells or myeloid derived suppressor cells (MDSCs), in an attempt to correct the balance between GVHD and GVT. MDSCs have been shown to be able to inhibit GVHD but not much is known about the ability of MDSCs to preserve GVT. We have previously shown that myeloid progenitors lacking Muc1 from Muc1 knockout (KO) C57BL/6 (H-2b) mice generate more effective MDSCs in vitro and in vivo. In this current study, we study the potential of using MDSCs generated in the absence of Muc1 to alleviate T cell expansion while preserving CTL activity. Our preliminary data shows that MDSCs generated from Muc1 KO C57BL/6 (H-2b) bone marrow are able to inhibit C57BL/6 (H-2b) T cell proliferation in an allogeneic mixed lymphocyte reaction, using Balb/c (H-2d) stimulators, more effectively than wildtype (WT) MDSCs. Interestingly, despite the reduced T cell proliferation in the presence of KO MDSCs, the CTL activity of these C57BL/6 T cells was still preserved, as demonstrated by their ability to lyse Balb/c A-20 leukemia cells. These results inidicate that co transplant of MDSCs generated in the absence of Muc1 can alleviate GVHD across fully mismatched major histocompatibility complex (MHC) barriers while still preserving the GVT ability of the allograft. This would also validate the clinical desirability of down regulating MUC1 in HSCs for more effective generation of MDSCs in a clinical allogeneic HSC transplantation setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1935.

Introduction: The H1N1 (subtype hemagglutinin 1 neuraminidase 1) influenza pandemic of 2009 was associated with a large increase in demand for primary care office visits. However, many patients with H1N1 symptoms or exposure could be assessed and treated with telephone protocols. Methods: Specific H1N1 influenza telephone protocols were developed by Mayo Clinic physicians using Centers for Disease Control recommendations. Using symptom calls to a primary care practice in the United States, we captured nurse telephone triage recommendations, telephone antiviral prescriptions, and what callers would have done without telephone advice. We retrospectively analyzed all symptom calls from July 2009 through January 2010. Results: Call volume was 5,596 calls monthly during the peak influenza months, which was 56% above the monthly average of 3,595 calls for the nonpeak months ( p < 0.001). The calls during October 2009 were 111% over the nonpeak months ( p < 0.001). In October 2009, telephone triage nurses gave 412 prescriptions for antivirals accounting for 5.4% of calls and 39% of all telephonic prescriptions for that month. In the peak H1N1 month of October, there were 1,522 callers who intended to stay home for their care. For the same month, triage nurses suggested 3,250 of the callers stay home. For an October 2009 appointment capacity of 35,126 visit slots, a potential 5% capacity was preserved. Conclusions: A telephone triage solution for the acute demands of influenza H1N1 demonstrated how patients had needs met telephonically while preserving medical access for others.

Abstract Recent studies have indicated that neutral collagenase can be produced in bones of rats. In addition, it has been demonstrated by in vitro studies that the enzyme is likely secreted by osteoblasts. Cells of the osteoblastic tumor cell line UMR-106 can be stimulated to produce not only collagenase, but also collagenase inhibitor and plasminogen activator. However, it is conceivable that not all osteoblasts produce all of these proteins. In this study, in which UMR cells were maximally stimulated with PTH, only a subpopulation of cells was observed to produce enhanced levels of collagenase but all cells had the ability to synthesize plasminogen activator. Cells of the rat osteosarcoma line UMR-106-01 were stained for the presence of collagenase and tissue plasminogen activator using an immunohistochemical procedure. In many cases, the cells were exposed to monensin for the final 3 h of incubation as well as to the inducing agent PTH. Monensin prevented export of the enzymes, enabling them to be visualized within their cell of origin. Maximal stimulation of collagenase was demonstrated to occur 8 h after exposure to 10−8-10−7 M PTH. Under these conditions, 14-17% of the cells appeared to synthesize elevated amounts of collagenase (as determined by intense staining). Without PTH stimulation, there was a low level of collagenase in all cells, but &lt; 1% of the cells stained heavily for the enzyme. In contrast, strong staining for plasminogen activator was observed in all cells with or without PTH treatment. This suggests that the regulation of collagenase production in osteoblasts occurs at the level of the individual cell such that there appear to be subpopulations of cells that respond differently to PTH stimulation.

Abstract Microvesicles (MVs) released by malignant cancer cells constitute an important part of the tumor microenvironment. They can transfer various messages to target cells and may be critical to disease progression. Here, we demonstrate that MVs circulating in plasma of B-cell chronic lymphocytic leukemia (CLL) patients exhibit a phenotypic shift from predominantly platelet derived in early stage to leukemic B-cell derived at advanced stage. Furthermore, the total MV level in CLL was significantly greater compared with healthy subjects. To understand the functional implication, we examined whether MVs can interact and modulate CLL bone marrow stromal cells (BMSCs) known to provide a “homing and nurturing” environment for CLL B cells. We found that CLL-MV can activate the AKT/mammalian target of rapamycin/p70S6K/hypoxia-inducible factor-1α axis in CLL-BMSCs with production of vascular endothelial growth factor, a survival factor for CLL B cells. Moreover, MV-mediated AKT activation led to modulation of the β-catenin pathway and increased expression of cyclin D1 and c-myc in BMSCs. We found MV delivered phospho-receptor tyrosine kinase Axl directly to the BMSCs in association with AKT activation. This study demonstrates the existence of separate MV phenotypes during leukemic disease progression and underscores the important role of MVs in activation of the tumor microenvironment.